Abstract

Conventional approaches to radiologic response assessment are inadequate for early therapy response assessment (ETRA) of glioblastoma multiforme (GBM), as they rely on slowly changing measures of therapeutic effect, e.g., changes in tumor size or in contrast enhancement on magnetic resonance imaging (MRI). Positron emission tomography (PET) imaging of GBM glucose metabolism using 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG) has exhibited some success in diagnostic imaging of GBM; however, false-positive uptake caused by inflammation at the tumor site as well as high background uptake in uninvolved brain tissue limits its use for ETRA.

2-(5-[18F]fluoro-pentyl)-2-methylmalonic acid ([18F]ML-10) has recently been proposed as a PET radiotracer for imaging apoptosis. Molecular imaging of apoptosis is an attractive approach to ETRA of GBM, as it would provide a direct measure of therapeutic effect and a framework within which to interpret and compare efficacies of competing therapies. Previous studies have demonstrated the safety and bioavailability of [18F]ML-10 in healthy humans. However, the pharmacokinetic (PK) properties of [18F]ML-10 have not been evaluated.

This dissertation examines the PK properties of [18F]ML-10 in a cohort of human subjects receiving treatment for GBM. [18F]ML-10 time-course in GBM was studied on a whole tumor and voxelwise level. [18F]ML-10 uptake was modeled as the response of a linear system using the radiotracer concentration in blood (measured from the PET image) as the input function (IF). In the whole tumor analysis, candidate models for the IF and GBM impulse response function (IRF) were fit simultaneously using a maximum likelihood approach. The relative merits of the joint IF/IRF models were compared using the Akaike information criterion and model parameter estimability considerations. Spectral analysis was performed to support model selection and provide alternative estimates of standard PK uptake measures. The selected IF/IRF models were further interpreted through tissue compartmental modeling. Standard PK measures of radiotracer uptake derived from models were evaluated for their utility in ETRA for a limited number of subjects. Finally, GBM heterogeneity in response to therapy was evaluated through a voxelwise analysis of [18F]ML-10 uptake. Comparison was made between [18F]ML-10 uptake at an ETRA time-point and later change in tumor cellularity measured using diffusion weighted MRI.